Spectrum of genital findings in ART-conceived male neonates: A blinded case series analyzing parental reproductive history

Background and objectives: An increase in genital abnormalities in boys born via assisted reproductive technologies (ART) is possibly linked to either the technical aspects of ART or parental health, regardless of the type of ART procedure. This study aimed to describe the spectrum and prevalence of genital findings in ART-conceived male infants and to identify potential modifiable factors associated with genital development in this subpopulation. Methods: An observational, exploratory/hypothesis-generating case series was conducted from August 2006 to July 2007. A total of 294 consecutively born male neonates were examined by a single urologist blinded to conception method. From this cohort, 71 infants conceived via ART were identified. Obstetrician-gynecologists retrieved detailed data on parental reproductive history and newborn health status. A nested comparative analysis was performed within the ART group, using the adjusted Wald-method and the two-sided Fisher’s exact test. Results: Forty boys (56%) in the study group had normal genitalia, whereas 31 (44%) displayed abnormalities. Singleton pregnancy was a significant protective factor for normal genitalia ( p = 0.004), while a non-significant trend was observed for the absence of maternal abnormalities other than obstructive infertility ( p = 0.282). Hypospadias prevalence (4.2%), in contrast to cryptorchidism and inguinal hernia, exceeded general population rates (0.06%–0.7%) and was an order of magnitude higher than in Denmark and Sweden (0.3%–0.4%). This increased prevalence was associated with male factor infertility ( p = 0.041) and with maternal subfertility in the form of preterm labor ( p = 0.032). The complex of penile malformations were linked to maternal endocrine infertility ( p = 0.033), dizygotic twins ( p = 0.014), and preterm labor ( p = 0.017), with non-significant trend for threatened miscarriage ( p = 0.107). Conclusion(s): This blinded case series reveals a distinct spectrum of genital findings in ART-conceived neonates, with high hypospadias prevalence. Penile development appears primarily linked to parental fertility issues and preterm labor. Singleton pregnancy is likely a strong protective factor. These findings indicate underlying parental subfertility as the potential determinant of genital malformation risk, with ART procedures as a possible confounder.